Human Genome and Diseases:¶The molecular pathogenesis of the Marfan syndrome

Abstract

The Marfan syndrome (MFS) is an autosomal dominant heritable disorder of connective tissue with highly variable clinical manifestations including aortic dilatation and dissection, ectopia lentis, and a range of skeletal anomalies. Mutations in the gene for fibrillin-1 (FBN1) cause MFS and other related disorders of connective tissue collectively termed type-1 fibrillinopathies. Fibrillin-1 is a main component of the 10- to 12-nm extracellular microfibrils that are important for elastogenesis, elasticity, and homeostasis of elastic fibers. Mutations in fibrillin-1 are hypothesized to exert their effects by dominant negative mechanisms, but recent work has also emphasized the potential role of proteases and disturbances in tissue homeostasis in the pathogenesis of the MFS. This article provides an overview of the clinical aspects of the MFS and current thinking on the pathogenesis of this disorder.

Homozygosity for a FBN1 missense mutation: clinical and molecular evidence for recessive Marfan syndrome

“…Mutations introducing an extra cysteine within this motif, such as in our family, are likely to cause domain misfolding, which may lead a defective global structure and function of the protein. 7 Clinically, this type of cysteine substitution mutations in a heterozygous state have been associated with a higher incidence of ectopia lentis compared to nonsense mutations leading to a premature stop codon. 6,13 In the family we describe here, this mutation in heterozygous state did not cause the MFS.…”

“…5,6 The MFS is known as an autosomal-dominant disorder (MIM 154700) and several studies in human and mice have, for a long time, favored a dominant-negative model for the pathogenesis of MFS. 7 However, recently, based on mice studies a role for a haplo-insuffiency model has been raised, 8 including the hypothesis that abnormal fibrillin or reduced levels of fibrillin may lead to an excess of TGF-b activity. 9 Here, we report on two cousins from a consanguineous Turkish family with a homozygous c.1453C4T FBN1 mutation (p.Arg485Cys) and MFS.…”

Tissue elasticity and the ageing elastic fibre

“…For interpretation of coloured elements within this figure please refer to the electronic version of the manuscript fibrillin microfibrils communicate with cells via an RGD (Arg-Gly-Asp) recognition site, which is bound by α 5 β 1 and α v β 3 integrins (Bax et al 2003). The importance of fibrillin in maintaining tissue function is highlighted by the severe ocular, skeletal and cardiovascular pathologies experienced by individuals suffering from Marfan syndrome, a heritable connective tissue disorder caused by mutations in fibrillin-1 (Robinson and Booms 2001).…”

“…In addition to heart failure, chronic hypertension is implicated as a major risk factor in the development of strokes (Nilsson 2005), renal failure (Lariviere and Lebel 2003) and aortic aneurysms (Lederle et al 2008). The fundamental role of elastic fibre components in maintaining arterial function is underlined by the severe clinical consequences of both fibrillin and tropoelastin mutations (Kielty et al 2002;Robinson and Booms 2001). Mutations in fibrillin-1, for example, cause Marfan syndrome, a heritable connective tissue disorder which is associated with ocular, skeletal, pulmonary and vascular defects.…”

“…It is these vascular pathologies which are primarily responsible for the markedly reduced life expectancy experienced by Marfan patients in the absence of modern medical interventions [32 ± 16 years (Silverman et al 1995)]. Dilatation, and ultimately, dissection, of the aortic root and/or ascending aorta being the main cause of death (Robinson and Booms 2001). Mutations in elastin can have an equally severe impact on morbidity and mortality giving rise to supravalvular aortic stenosis (SVAS), which in turn can cause left ventricular hypertrophy and ultimately congestive heart failure (Milewicz et al 2000).…”